RESUMO
Genome-wide association studies (GWASs) have identified several susceptibility loci for bipolar disorder (BD) and shown that the genetic architecture of BD can be explained by polygenicity, with numerous variants contributing to BD. In the present GWAS (Phase I/II), which included 2964 BD and 61 887 control subjects from the Japanese population, we detected a novel susceptibility locus at 11q12.2 (rs28456, P=6.4 × 10-9), a region known to contain regulatory genes for plasma lipid levels (FADS1/2/3). A subsequent meta-analysis of Phase I/II and the Psychiatric GWAS Consortium for BD (PGC-BD) identified another novel BD gene, NFIX (Pbest=5.8 × 10-10), and supported three regions previously implicated in BD susceptibility: MAD1L1 (Pbest=1.9 × 10-9), TRANK1 (Pbest=2.1 × 10-9) and ODZ4 (Pbest=3.3 × 10-9). Polygenicity of BD within Japanese and trans-European-Japanese populations was assessed with risk profile score analysis. We detected higher scores in BD cases both within (Phase I/II) and across populations (Phase I/II and PGC-BD). These were defined by (1) Phase II as discovery and Phase I as target, or vice versa (for 'within Japanese comparisons', Pbest~10-29, R2~2%), and (2) European PGC-BD as discovery and Japanese BD (Phase I/II) as target (for 'trans-European-Japanese comparison,' Pbest~10-13, R2~0.27%). This 'trans population' effect was supported by estimation of the genetic correlation using the effect size based on each population (liability estimates~0.7). These results indicate that (1) two novel and three previously implicated loci are significantly associated with BD and that (2) BD 'risk' effect are shared between Japanese and European populations.
Assuntos
Transtorno Bipolar/genética , Adulto , Proteínas de Ciclo Celular/genética , Citocinas/genética , Dessaturase de Ácido Graxo Delta-5 , Ácidos Graxos Dessaturases/genética , Feminino , Predisposição Genética para Doença/genética , Estudo de Associação Genômica Ampla , Humanos , Japão/epidemiologia , Masculino , Glicoproteínas de Membrana/genética , Pessoa de Meia-Idade , Herança Multifatorial/genética , Fatores de Transcrição NFI/genética , Proteínas Nucleares/genética , Polimorfismo de Nucleotídeo Único/genéticaRESUMO
We report on new results of a search for a two-photon interaction with axionlike particles (ALPs). The experiment is carried out at a synchrotron radiation facility using a "light shining through a wall (LSW)" technique. For this purpose, we develop a novel pulsed-magnet system, composed of multiple racetrack magnets and a transportable power supply. It produces fields of about 10 T over 0.8 m with a high repetition rate of 0.2 Hz and yields a new method of probing a vacuum with high intensity fields. The data obtained with a total of 27 676 pulses provide a limit on the ALP-two-photon coupling constant that is more stringent by a factor of 5.2 compared to a previous x-ray LSW limit for the ALP mass â²0.1 eV.
RESUMO
OBJECTIVES: This study aimed to investigate the features, treatments, and prognosis of patients with symptomatic and asymptomatic isolated SMA dissection. METHODS: Data from 35 consecutive patients in whom isolated SMA dissection was diagnosed on computed tomography angiography (CTA) between 2004 and 2015 at two general hospitals in Japan, were collected retrospectively. Nineteen symptomatic patients were compared, and 16 asymptomatic patients with incidentally revealed SMA dissection were also compared. In addition, the vascular remodelling and outcomes during follow-up were evaluated. RESULTS: The patient characteristics in the symptomatic and incidental groups were comparable except for age; mean ages were 55.9 ± 13.9 and 65.3 ± 10.9 years, respectively. Most of the symptomatic patients were managed conservatively (including antiplatelet therapy, anticoagulants, blood pressure control, or bowel rest). In addition, one patient was initially treated by endovascular intervention because of intestinal ischaemia, and another was switched from conservative to surgical treatment. The in-hospital outcome was good with no mortality. In the incidental group, all 16 patients were observed as outpatients without additional treatment. Complete remodelling of the false lumen was observed in 31% of patients with follow-up CTA, and was associated with the presence of symptoms and the absence of false lumen with blood flow at diagnosis. Neither recurrent or new onset abdominal pain, intervention for SMA dissection, nor SMA related death was observed in either group during the follow-up period (750 ± 779 and 1200 ± 951 days). CONCLUSIONS: The characteristics of asymptomatic patients with incidentally revealed SMA dissection were comparable with those of symptomatic patients, except for age. During follow-up, factors favouring complete remodelling of false lumens were the presence of symptoms, and the absence of false lumen blood flow at diagnosis.
Assuntos
Dissecção Aórtica/diagnóstico por imagem , Dissecção Aórtica/terapia , Fármacos Cardiovasculares/uso terapêutico , Procedimentos Endovasculares , Artéria Mesentérica Superior/diagnóstico por imagem , Artéria Mesentérica Superior/cirurgia , Procedimentos Cirúrgicos Vasculares , Adulto , Idoso , Dissecção Aórtica/fisiopatologia , Fármacos Cardiovasculares/efeitos adversos , Angiografia por Tomografia Computadorizada , Procedimentos Endovasculares/efeitos adversos , Feminino , Hospitais Gerais , Humanos , Achados Incidentais , Japão , Masculino , Artéria Mesentérica Superior/fisiopatologia , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Estudos Retrospectivos , Fatores de Risco , Fatores de Tempo , Resultado do Tratamento , Remodelação Vascular , Procedimentos Cirúrgicos Vasculares/efeitos adversosRESUMO
Opioids, such as morphine and fentanyl, are widely used as effective analgesics for the treatment of acute and chronic pain. In addition, the opioid system has a key role in the rewarding effects of morphine, ethanol, cocaine and various other drugs. Although opioid sensitivity is well known to vary widely among individual subjects, several candidate genetic polymorphisms reported so far are not sufficient for fully understanding the wide range of interindividual differences in human opioid sensitivity. By conducting a multistage genome-wide association study (GWAS) in healthy subjects, we found that genetic polymorphisms within a linkage disequilibrium block that spans 2q33.3-2q34 were strongly associated with the requirements for postoperative opioid analgesics after painful cosmetic surgery. The C allele of the best candidate single-nucleotide polymorphism (SNP), rs2952768, was associated with more analgesic requirements, and consistent results were obtained in patients who underwent abdominal surgery. In addition, carriers of the C allele in this SNP exhibited less vulnerability to severe drug dependence in patients with methamphetamine dependence, alcohol dependence, and eating disorders and a lower 'Reward Dependence' score on a personality questionnaire in healthy subjects. Furthermore, the C/C genotype of this SNP was significantly associated with the elevated expression of a neighboring gene, CREB1. These results show that SNPs in this locus are the most potent genetic factors associated with human opioid sensitivity known to date, affecting both the efficacy of opioid analgesics and liability to severe substance dependence. Our findings provide valuable information for the personalized treatment of pain and drug dependence.
Assuntos
Analgésicos Opioides/administração & dosagem , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/genética , Dor Pós-Operatória/tratamento farmacológico , Dor Pós-Operatória/genética , Polimorfismo de Nucleotídeo Único/genética , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Cromossomos Humanos Par 2/genética , Metilases de Modificação do DNA/genética , Feminino , Estudo de Associação Genômica Ampla , Genótipo , Humanos , Desequilíbrio de Ligação , Masculino , Pessoa de Meia-Idade , Medição da Dor , Dor Pós-Operatória/etiologia , Escalas de Graduação Psiquiátrica , Procedimentos de Cirurgia Plástica/efeitos adversos , Transtornos Relacionados ao Uso de Substâncias/genética , Adulto JovemRESUMO
We implemented a two-step approach to detect potential predictor gene variants for neuroleptic-induced tardive dyskinesia (TD) in schizophrenic subjects. First, we screened associations by using a genome-wide (Illumina HumanHapCNV370) SNP array in 61 Japanese schizophrenia patients with treatment-resistant TD and 61 Japanese schizophrenia patients without TD. Next, we performed a replication analysis in 36 treatment-resistant TD and 138 non-TD subjects. An association of an SNP in the DPP6 (dipeptidyl peptidase-like protein-6) gene, rs6977820, the most promising association identified by the screen, was significant in the replication sample (allelic P=0.008 in the replication sample, allelic P=4.6 × 10(-6), odds ratio 2.32 in the combined sample). The SNP is located in intron-1 of the DPP6 gene and the risk allele was associated with decreased DPP6 gene expression in the human postmortem prefrontal cortex. Chronic administration of haloperidol increased Dpp6 expression in mouse brains. DPP6 is an auxiliary subunit of Kv4 and regulates the properties of Kv4, which regulates the activity of dopaminergic neurons. The findings of this study indicate that an altered response of Kv4/DPP6 to long-term neuroleptic administration is involved in neuroleptic-induced TD.
Assuntos
Antipsicóticos/efeitos adversos , Dipeptidil Peptidases e Tripeptidil Peptidases/genética , Discinesia Induzida por Medicamentos/genética , Proteínas do Tecido Nervoso/genética , Canais de Potássio/genética , Alelos , Animais , Antipsicóticos/uso terapêutico , Povo Asiático , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Dipeptidil Peptidases e Tripeptidil Peptidases/metabolismo , Discinesia Induzida por Medicamentos/metabolismo , Feminino , Expressão Gênica , Genótipo , Humanos , Íntrons , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Pessoa de Meia-Idade , Proteínas do Tecido Nervoso/metabolismo , Polimorfismo de Nucleotídeo Único , Canais de Potássio/metabolismo , Esquizofrenia/tratamento farmacológicoRESUMO
Osteoclasts are terminally differentiated cells derived from hematopoietic stem cells. However, how their precursor cells diverge from macrophagic lineages is not known. We have identified early and late stages of osteoclastogenesis, in which precursor cells sequentially express c-Fms followed by receptor activator of nuclear factor kappaB (RANK), and have demonstrated that RANK expression in early-stage of precursor cells (c-Fms(+)RANK(-)) was stimulated by macrophage colony-stimulating factor (M-CSF). Although M-CSF and RANKL (ligand) induced commitment of late-stage precursor cells (c-Fms(+)RANK(+)) into osteoclasts, even late-stage precursors have the potential to differentiate into macrophages without RANKL. Pretreatment of precursors with M-CSF and delayed addition of RANKL showed that timing of RANK expression and subsequent binding of RANKL are critical for osteoclastogenesis. Thus, the RANK-RANKL system determines the osteoclast differentiation of bipotential precursors in the default pathway of macrophagic differentiation.
Assuntos
Proteínas de Transporte , Linhagem da Célula/fisiologia , Fator Estimulador de Colônias de Macrófagos/fisiologia , Glicoproteínas de Membrana , Osteoclastos/citologia , Osteoclastos/fisiologia , Receptor de Fator Estimulador de Colônias de Macrófagos/fisiologia , Receptores do Fator de Necrose Tumoral/fisiologia , Animais , Diferenciação Celular/fisiologia , Células-Tronco Hematopoéticas/fisiologia , Ligantes , Macrófagos/citologia , Macrófagos/fisiologia , Camundongos , Camundongos Endogâmicos C57BL , Ligante RANK , Receptor Ativador de Fator Nuclear kappa-BRESUMO
Chromosome 1p13 is linked with schizophrenia in Japanese families, and one of the candidate genes in this region is the netrin G1 (NTNG1) gene at 1p13.3. Associations of 56 tag single-nucleotide polymorphisms (SNPs) with schizophrenia were explored by transmission disequilibrium analysis in 160 Japanese trios and by case-control analysis in 2,174 Japanese cases and 2,054 Japanese controls. An association between SNP rs628117 and schizophrenia was identified by case-control comparison (nominal allelic p=0.0009; corrected p=0.006). The associated polymorphism is located in intron 9 and in the haplotype block encompassing the alternatively spliced exons of the gene. Allelic association of a different SNP in the same haplotype block in Japanese families was previously reported. These findings support that the NTNG1 gene is associated with schizophrenia in the Japanese.
Assuntos
Cromossomos Humanos Par 1/genética , Éxons , Predisposição Genética para Doença , Glicoproteínas/genética , Proteínas do Tecido Nervoso/genética , Polimorfismo de Nucleotídeo Único , Esquizofrenia/genética , Adulto , Estudos de Casos e Controles , Distribuição de Qui-Quadrado , Feminino , Proteínas Ligadas por GPI , Frequência do Gene , Haplótipos , Humanos , Japão , Masculino , Pessoa de Meia-Idade , Netrinas , Splicing de RNARESUMO
Recent investigations suggest that the AKT/glycogen synthase kinase 3 (GSK3) signaling cascade may be associated with the pathophysiology of schizophrenia and methamphetamine (METH) use disorder. One important molecule related to this cascade is beta-arrestin 2 (ARRB2). We therefore conducted a genetic case-control association analysis of the gene for ARRB2 with schizophrenia and METH use disorder in a Japanese population (547 people with schizophrenia, 177 with METH use disorder and 546 controls). A possible association of 'tag single nucleotide polymorphisms (SNPs)' was found in METH use disorder (rs1045280: P(genotype) = 0.0118, P(allele) = 0.00351; rs2036657: P(allele) = 0.0431; rs4790694: P(genotype) = 0.0167, P(allele) = 0.0202), but no association was found with schizophrenia. We also evaluated the gene-gene interactions among ARRB2, AKT1, and GSK3B, which we previously reported for each of these diseases. However, no interaction was seen in our samples. This is the first association analysis of ARRB2, and our results indicate that ARRB2 may play a role in the pathophysiology of METH use disorder.
Assuntos
Transtornos Relacionados ao Uso de Anfetaminas/genética , Arrestinas/genética , Esquizofrenia/genética , Adulto , Transtornos Relacionados ao Uso de Anfetaminas/metabolismo , Arrestinas/metabolismo , Estudos de Casos e Controles , Distribuição de Qui-Quadrado , Feminino , Humanos , Desequilíbrio de Ligação , Masculino , Metanfetamina , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único/genética , Esquizofrenia/metabolismo , beta-Arrestina 2 , beta-ArrestinasRESUMO
BACKGROUND: This prospective randomized study compared the survival of patients with tumour node metastasis (TNM) stage T2 N1-2 gastric cancer treated by gastrectomy alone or gastrectomy followed by uracil-tegafur. METHODS: Patients were randomly assigned to surgery alone or to surgery and postoperative uracil-tegafur 360 mg per m(2) per day orally for 16 months. The primary endpoint was overall survival. Relapse-free survival and site of recurrence were secondary endpoints. RESULTS: Of 190 registered patients, 95 were randomized to each group; two patients with early cancer were subsequently excluded from the chemotherapy group. The trial was terminated before the target number of patients was reached because accrual was slower than expected. Drug-related adverse effects were mild, with no treatment-related deaths. At a median follow-up of 6.2 years, overall and relapse-free survival rates were significantly higher in the chemotherapy group (hazard ratio for overall survival 0.48, P = 0.017; hazard ratio for relapse-free survival 0.44, P = 0.005), confirming the survival benefit shown in an interim analysis performed 2 years earlier. CONCLUSION: Interim and final analyses revealed a significant survival benefit for postoperative adjuvant chemotherapy with uracil-tegafur in patients with serosa-negative, node-positive gastric cancer. REGISTRATION NUMBER: NCT00152243 (http://www.clinicaltrials.gov).
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Gastrectomia/métodos , Neoplasias Gástricas/terapia , Quimioterapia Adjuvante , Intervalo Livre de Doença , Feminino , Humanos , Excisão de Linfonodo , Metástase Linfática , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Tegafur/administração & dosagem , Uracila/administração & dosagemRESUMO
The regulator of the G-protein signaling 4 (RGS4) has been implicated in the susceptibility to schizophrenia. RGS4 interacts with ErbB3 that acts as receptors for neuregulin 1 and these proteins may play a role in the pathogenesis of schizophrenia via glutamatergic dysfunction. Recently, two meta-analysis studies provided different interpretations for the genetic association between RGS4 and schizophrenia. We attempted to confirm this association in a case-control study of 1918 Japanese patients with schizophrenia and 1909 Japanese control subjects. Four widely studied single nucleotide polymorphisms (SNPs) were genotyped, and none showed association with schizophrenia. SNP 1 (rs10917670), p=0.92; SNP 4 (rs951436), p=0.91; SNP 7 (rs951439), p=0.27; and SNP 18 (rs2661319), p=0.43. A haplotype block constructed by these SNPs spans the 5' flanking region to the 5' mid-region of the RGS4 gene. Previous meta-analysis showed that both two major haplotypes of this block were risk haplotypes. The two common haplotypes were observed in the Japanese population. However, neither haplotype was significantly associated with schizophrenia. We conclude that the common haplotypes and SNPs of the RGS4 gene identified thus far are unlikely to contribute to the genetic susceptibility to schizophrenia in the Japanese population.
Assuntos
Povo Asiático/genética , Predisposição Genética para Doença/genética , Proteínas RGS/genética , Esquizofrenia/genética , Adulto , Idoso , Estudos de Casos e Controles , Feminino , Genótipo , Haplótipos , Humanos , Japão , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único/genética , Esquizofrenia/diagnósticoRESUMO
The protein interacting with C-kinase 1 (PICK1) has been implicated in the susceptibility to schizophrenia. PICK1 interacts with enzymes and receptors that play roles in the pathogenesis of schizophrenia via glutamatergic dysfunction. Recently, two studies reported associations between schizophrenia and two PICK1 gene polymorphisms, rs3952 in Chinese and Japanese populations and rs2076369 in a Japanese population. We attempted to confirm these associations in a case-control study of 1765 Japanese patients with schizophrenia and 1851 Japanese control subjects. Neither polymorphism was associated with schizophrenia (rs3952, p=0.755; rs2076369, p=0.997). A haplotype block with these polymorphisms spanning the 5' region of the PICK1 gene showed high linkage disequilibrium in the Japanese population (D'=0.98, r(2)=0.34); however, neither haplotype was significantly associated with schizophrenia. We conclude that the common haplotypes and polymorphisms of the PICK1 gene identified thus far are unlikely to contribute to genetic susceptibility to schizophrenia in the Japanese population.
Assuntos
Proteínas de Transporte/genética , Predisposição Genética para Doença , Proteínas Nucleares/genética , Polimorfismo Genético , Esquizofrenia/genética , Adulto , Alelos , Feminino , Frequência do Gene , Genótipo , Humanos , Japão/epidemiologia , Masculino , Pessoa de Meia-IdadeRESUMO
Reticulon 4 receptor (RTN4R) plays an essential role in regulating axonal regeneration and plasticity in the central nervous system through the activation of rho kinase, and is located within chromosome 22q11.2, a region that is known to be a hotspot for schizophrenia (SCZ) and autism spectrum disorder (ASD). Recently, rare variants such as copy-number variants and single-nucleotide variants have been a focus of research because of their large effect size associated with increased susceptibility to SCZ and ASD and the possibility of elucidating the pathophysiology of mental disorder through functional analysis of the discovered rare variants. To discover rare variants with large effect size and to evaluate their role in the etiopathophysiology of SCZ and ASD, we sequenced the RTN4R coding exons with a sample comprising 370 SCZ and 192 ASD patients, and association analysis using a large number of unrelated individuals (1716 SCZ, 382 ASD and 4009 controls). Through this mutation screening, we discovered four rare (minor allele frequency <1%) missense mutations (R68H, D259N, R292H and V363M) of RTN4R. Among these discovered rare mutations, R292H was found to be significantly associated with SCZ (P=0.048). Furthermore, in vitro functional assays showed that the R292H mutation affected the formation of growth cones. This study strengthens the evidence for association between rare variants within RTN4R and SCZ, and may shed light on the molecular mechanisms underlying the neurodevelopmental disorder.
Assuntos
Transtorno do Espectro Autista/genética , Receptor Nogo 1/genética , Esquizofrenia/genética , Adolescente , Adulto , Transtorno do Espectro Autista/fisiopatologia , Criança , Éxons , Feminino , Frequência do Gene , Cones de Crescimento/metabolismo , Humanos , Masculino , Pessoa de Meia-Idade , Mutação , Mutação de Sentido Incorreto , Polimorfismo de Nucleotídeo Único/genética , Esquizofrenia/fisiopatologia , Adulto Jovem , Quinases Associadas a rho/metabolismoRESUMO
CX3CR1, a G protein-coupled receptor solely expressed by microglia in the brain, has been repeatedly reported to be associated with neurodevelopmental disorders including schizophrenia (SCZ) and autism spectrum disorders (ASD) in transcriptomic and animal studies but not in genetic studies. To address the impacts of variants in CX3CR1 on neurodevelopmental disorders, we conducted coding exon-targeted resequencing of CX3CR1 in 370 Japanese SCZ and 192 ASD patients using next-generation sequencing technology, followed by a genetic association study in a sample comprising 7054 unrelated individuals (2653 SCZ, 574 ASD and 3827 controls). We then performed in silico three-dimensional (3D) structural modeling and in vivo disruption of Akt phosphorylation to determine the impact of the detected variant on CX3CR1-dependent signal transduction. We detected a statistically significant association between the variant Ala55Thr in CX3CR1 with SCZ and ASD phenotypes (odds ratio=8.3, P=0.020). A 3D structural model indicated that Ala55Thr could destabilize the conformation of the CX3CR1 helix 8 and affect its interaction with a heterotrimeric G protein. In vitro functional analysis showed that the CX3CR1-Ala55Thr mutation inhibited cell signaling induced by fractalkine, the ligand for CX3CR1. The combined data suggested that the variant Ala55Thr in CX3CR1 might result in the disruption of CX3CR1 signaling. Our results strengthen the association between microglia-specific genes and neurodevelopmental disorders.
Assuntos
Transtorno do Espectro Autista/genética , Receptor 1 de Quimiocina CX3C/genética , Esquizofrenia/genética , Adolescente , Adulto , Idoso , Criança , Simulação por Computador , Éxons , Feminino , Estudos de Associação Genética , Predisposição Genética para Doença , Genótipo , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Masculino , Pessoa de Meia-Idade , Mutação , Polimorfismo de Nucleotídeo Único , Adulto JovemRESUMO
Several lines of evidence suggest that metabolic changes in the kynurenic acid (KYNA) pathway are related to the etiology of schizophrenia. The inhibitor of kynurenine 3-monooxygenase (KMO) is known to increase KYNA levels, and the KMO gene is located in the chromosome region associated with schizophrenia, 1q42-q44. Single-marker and haplotype analyses for 6-tag single nucleotide polymorphisms (SNPs) of KMO were performed (cases = 465, controls = 440). Significant association of rs2275163 with schizophrenia was observed by single-marker comparisons (P = 0.032) and haplotype analysis including this SNP (P = 0.0049). Significant association of rs2275163 and haplotype was not replicated using a second, independent set of samples (cases = 480, controls = 448) (P = 0.706 and P = 0.689, respectively). These results suggest that the KMO is unlikely to be related to the development of schizophrenia in Japanese.
Assuntos
Cromossomos Humanos Par 1/genética , Predisposição Genética para Doença , Quinurenina 3-Mono-Oxigenase/genética , Esquizofrenia/genética , Idoso , Estudos de Casos e Controles , Distribuição de Qui-Quadrado , Epigênese Genética , Feminino , Frequência do Gene , Humanos , Japão , Ácido Cinurênico/metabolismo , Quinurenina 3-Mono-Oxigenase/metabolismo , Desequilíbrio de Ligação , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único/genéticaRESUMO
Dihydropyrimidinase-related protein 2 (DRP-2 or DPYSL-2)mediates the intracellular response to collapsin, a repulsive extracellular guidance cue or axonal outgrowth. DRP-2 is also referred to as collapsin response mediator protein 2 (CRMP-2). We have previously demonstrated that the DRP-2 gene is associated with susceptibility to schizophrenia, but not to bipolar disorders. In addition, a genetic association was observed with paranoid-type schizophrenia, but not with hebephrenic-type schizophrenia. It has been well documented that repeated abuse of methamphetamine (METH) for a long period frequently produces psychotic symptoms, such as auditory hallucinations and delusions that are hardly distinguishable from those of paranoid-type schizophrenia. Therefore, we hypothesized that a certain genetic variant of the DRP-2 gene may affect individual vulnerability to the development of METH-induced psychosis. We examined the genetic association by a case-control method. The polymorphism *2236T>C in the 3' untranslated region of the DRP-2 gene, which has been shown to be a negative genetic risk factor for paranoid-type schizophrenia, was analyzed in 198 patients with METH psychosis and 221 corresponding healthy controls in a Japanese population. No significant association of the DRP-2 gene with METH psychosis was found. Neither did we find an association with the clinical phenotype of METH psychosis, such as the age of first consumption of METH, latency to development of psychosis after METH abuse, prognosis of psychosis after detoxification from METH use, complication of spontaneous relapse of psychosis without reconsumption of the drug, or multisubstance abuse status. These findings indicate that a genetic variant of the DRP-2 gene may not affect the risk of METH psychosis or any clinical phenotype of the disorder.
Assuntos
Transtornos Relacionados ao Uso de Anfetaminas/genética , Dopaminérgicos/farmacologia , Frequência do Gene , Peptídeos e Proteínas de Sinalização Intercelular/genética , Metanfetamina/farmacologia , Proteínas do Tecido Nervoso/genética , Polimorfismo de Nucleotídeo Único , Adulto , Transtornos Relacionados ao Uso de Anfetaminas/etiologia , Estudos de Casos e Controles , Feminino , Humanos , Masculino , Pessoa de Meia-IdadeRESUMO
Recent preclinical findings that repeated treatment with methamphetamine (METH) induced an increase in tumor necrosis factor-alpha (TNF-alpha) mRNA in some brain regions and that TNF-alpha blocked METH neurotoxicity and rewarding effects suggest TNF-alpha, a multifunctional pro-inflammatory cytokine, may be involved in METH dependence. We hypothesized that genetic polymorphisms of the TNF-alpha gene and its receptor genes may be associated with vulnerability to METH dependence. Genetic association of -308G>A and -857C>T in the promotor region of the TNF-alpha gene, and 36A>G in exon 1 of the TNF receptor 1A gene (TNFR-SF1A), were analyzed in patients with METH dependence (n = 185) and healthy controls (n = 221) in a Japanese population. No significant association of alleles or haplotypes of the TNF-alpha or TNFR-SF1A genes with METH dependence was found. Neither was any significant association of clinical phenotype with METH dependence found. These results suggest that genetic variations in the TNF-alpha gene and its receptor genes may not be involved in individual vulnerability to METH dependence.
Assuntos
Transtornos Relacionados ao Uso de Anfetaminas/genética , Dopaminérgicos/farmacologia , Metanfetamina/farmacologia , Receptores Tipo I de Fatores de Necrose Tumoral/genética , Fator de Necrose Tumoral alfa/genética , Adulto , Estudos de Casos e Controles , Feminino , Frequência do Gene , Haplótipos , Humanos , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo ÚnicoRESUMO
Cocaine- and amphetamine-regulated transcript (CART) was originally discovered as a peptide that increased in the rat striatum after injection of a psychostimulant drug, such as cocaine or amphetamine, and is suggested to play potential roles in drug dependence. We tested the genetic association between the CART gene and methamphetamine (METH) dependence and/or psychosis. The subjects were 203 patients with METH dependence and 239 age- and gender-matched healthy controls. Two single nucleotide polymorphisms (SNPs) of the CART gene, -156A>G and IVS1 + 224G>A, were examined . There were no significant differences in genotype and allele distributions of the polymorphisms between patients with METH dependence and/or psychosis and controls. Neither were significant differences in subgroups of clinical phenotypes, for example, age at first consumption of METH, latency to onset of psychotic symptoms after the first consumption of METH, prognosis of psychosis after therapy, complication of spontaneous relapse to a psychotic state, or multisubstance abuse status, observed. The present findings suggest that the CART gene may not play a pivotal role in the development of METH dependence and psychosis, at least in a Japanese population.
Assuntos
Transtornos Relacionados ao Uso de Anfetaminas/genética , Predisposição Genética para Doença , Proteínas do Tecido Nervoso/genética , Polimorfismo Genético , Adulto , Alelos , Estudos de Casos e Controles , Feminino , Frequência do Gene , Humanos , Masculino , Pessoa de Meia-Idade , Psicoses Induzidas por Substâncias/genéticaRESUMO
Gastrointestinal motility disturbances during endotoxemia are probably caused by lipopolysaccharide (LPS)-induced factors: candidates include nitric oxide (NO), tumor necrosis factor-alpha (TNF-alpha), interleukin-1ss, and interleukin-6. Flow cytometry was used to determine the effects of LPS and these factors on gastric emptying (evaluated indirectly by determining percent gastric retention; %GR) and gastrointestinal transit (GIT) in male BALB/c mice (23-28 g). NO (300 microg/mouse, N = 8) and TNF-alpha (2 microg/mouse, N = 7) increased (P < 0.01) GR and delayed GIT, mimicking the effect of LPS (50 microg/mouse). During early endotoxemia (1.5 h after LPS), inhibition of inducible NO synthase (iNOS) by a selective inhibitor, 1400 W (150 microg/mouse, N = 11), but not antibody neutralization of TNF-alpha (200 microg/mouse, N = 11), reversed the increase of GR (%GR 78.8 +/- 3.3 vs 47.2 +/- 7.5%) and the delay of GIT (geometric center 3.7 +/- 0.4 vs 5.6 +/- 0.2). During late endotoxemia (8 h after LPS), both iNOS inhibition (N = 9) and TNF-alpha neutralization (N = 9) reversed the increase of GR (%GR 33.7 +/- 2.0 vs 19.1 +/- 2.6% (1400 W) and 20.1 +/- 2.0% (anti-TNF-alpha)), but only TNF-alpha neutralization reversed the delay of GIT (geometric center 3.9 +/- 0.4 vs 5.9 +/- 0.2). These findings suggest that iNOS, but not TNF-alpha, is associated with delayed gastric emptying and GIT during early endotoxemia and that during late endotoxemia, both factors are associated with delayed gastric emptying, but only TNF-alpha is associated with delayed GIT.
Assuntos
Endotoxemia/fisiopatologia , Esvaziamento Gástrico/efeitos dos fármacos , Trânsito Gastrointestinal/efeitos dos fármacos , Lipopolissacarídeos/farmacologia , Óxido Nítrico Sintase Tipo II/efeitos dos fármacos , Fator de Necrose Tumoral alfa/efeitos dos fármacos , Animais , Western Blotting , Modelos Animais de Doenças , Ensaio de Imunoadsorção Enzimática , Citometria de Fluxo , Esvaziamento Gástrico/fisiologia , Trânsito Gastrointestinal/fisiologia , Interleucina-1beta/metabolismo , Interleucina-6/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Óxido Nítrico Sintase Tipo II/metabolismo , Fator de Necrose Tumoral alfa/metabolismoRESUMO
HTK is a receptor tyrosine kinase that belongs to the Eph subfamily. An extensive screening using BIAcore system revealed that a colon cancer cell line, C-1, expressed the ligand for HTK. From the conditioned medium of C-1 cells, a soluble form of ligand was purified by receptor affinity chromatography, and the isolation of full-length cDNA revealed that this ligand is identical to the human HTK ligand (HTKL) previously reported. HTK receptor tyrosine phosphorylation was induced by membrane-bound or clustered soluble HTKL but not by unclustered soluble HTKL, indicating that HTKL requires cell-to-cell interaction for receptor activation. Binding analysis demonstrated that HTKL binds to HTK with a much higher affinity (Kd: 1.23 nM) than the other transmembrane-type ligand for Eph family, LERK-2/ELKL (Kd: 135 nM). The expression of HTK in cord blood cells was upregulated after the culture in the presence of stem cell factor. Clustered soluble HTKL stimulated the proliferation of sorted HTK+ cord blood cells and a hematopoietic cell line, UT-7/EPO from which HTK was isolated. These findings suggest the involvement of HTK-HTKL system in the proliferation of HTK+ hematopoietic progenitor cells in the hematopoietic environment.
Assuntos
Sangue Fetal/metabolismo , Proteínas de Membrana/metabolismo , Receptores Proteína Tirosina Quinases/metabolismo , Sequência de Aminoácidos , Sequência de Bases , Linhagem Celular , Clonagem Molecular , Primers do DNA , DNA Complementar , Efrina-B2 , Sangue Fetal/citologia , Humanos , Ligantes , Proteínas de Membrana/genética , Dados de Sequência Molecular , Receptor EphB4 , Proteínas Recombinantes/metabolismoRESUMO
OBJECTIVES: The purpose of this study is to investigate the role of endogenous endothelin-1 (ET-1) in myocardial growth in Bio 14.6 Syrian cardiomyopathic hamsters (Bio). BACKGROUND: While ET-1, as a growth-promoting peptide, has been implicated in the development of secondary cardiac hypertrophy, the role of endogenous ET-1 in cardiac growth in primary myocardial disease is unknown. METHODS: We measured left ventricular ET-1 levels by a specific sandwich enzyme-linked immunosorbent assay. Furthermore, we examined the chronic effect of T0201, an ET type A receptor-specific antagonist. RESULTS: The ET-1 levels in the left ventricles were 1.8-fold higher (p < 0.0005) at 20 weeks and 6.4-fold higher (p < 0.0001) at 35 weeks in the Bio compared to age-matched control F1B hamsters (F1B). The Bio ET-1 levels in the lungs exhibited an only 1.3-fold elevation at 35 weeks. Immunohistochemistry demonstrated the localization of ET-1 mainly in the cardiac myocytes. The treatment with T0201 significantly reduced the heart weight/body weight ratio in the Bio, but did not affect the heart weight/body weight ratio in the F1B. Histologically, T0201 reduced the myocyte diameter of Bio to a level similar with that of F1B. However, T0201 did not affect the extent of fibrosis in Bio or F1B. CONCLUSIONS: The ET-1 level in the heart of cardiomyopathic hamsters increases in stage-dependent and organ-specific manners. Though myocyte degeneration and subsequent replacement fibrosis do not require an ET-1 pathway, the accelerated synthesis of ET-1 in the heart may contribute to the pathological growth of remaining myocytes in this animal model.